Drugs act in such a way that drug molecules taken from the mouth or injected reach to a specific cell in the body and stimulate the cell. However, practically only a part of the drug administered can reach to a region to be acted, and thereby most of the drug is evacuated as it is from the body or it always acts normal cells to cause side-effects.
Therefore, it is ideal that a necessary amount of drugs can be sent to necessary cells at a necessary time. In the study for controlling the drug effect by utilizing various materials for attaining the object, there is a drug delivery system (DDS). Until now, investigation and development have been carried out by various approaches.
The objects of DDS are to release drugs over a definite period of time at a definite rate (formation of sustained release), to prolong the life of a drug having a short half-life in vivo, to promote the absorption of drugs from the keratin of the skin or the mucous membrane tissue, and to drug targeting of aiming at only a target cell. Among the objects, the sustained release of drugs has widely been attempted conventionally.
For example, the formation of sustained release functions of drugs from hydrogel of vivo absorption high-molecular weight compounds such as polylactic acid carriers etc., are studied (Advanced Drug Delivery Review, 2002, 43, 3-12). For the second object, there are a report on modification of drugs by water-soluble polymers, PEG etc. (Pharmazie, 2002 January 57(1), 5-29) and a report of utilizing PEG-modified liposome etc. (JP-A-11 (1999)-171771, Nippon Rinsho 1998 March, 56(3), 632-637). For the drug targeting, there are attempts to use polymers, antibody or liposome (Crit Rev Ther Drug Carrier Syst., 1987, 3(3), 233-261).
In the formation of sustained release functions of drugs by the use of hydrogel, the formation of sustained release is regulated by self-diffusion of a drug in an aqueous phase in the hydrogel. Therefore, it is difficult to control sustained release patterns, for example, it is very difficult to perform the formation of sustained release functions of a water-soluble drug over 3 or more days although it depends on a molecule size of the drug or its water solubility. In the diffusion-controlled drug sustained release system, in the case that the hydrogel which is a carrier for the formation of sustained release has a small size capable of administration with injection, the hydrogel carrier has a large surface per volume and a drug is released for a short period of time so that it is more difficult to perform the formation of sustained release of the drug. Further, in the case that the hydrogel carrier has a nanometer size capable of applying for intravenous administration, it is practically impossible to perform the formation of sustained release of a drug.
For sustained release of a water-soluble drug such as protein, gene etc., from the hydrogel, it is reported that the drug is physically fixed inside a gel and the formation of sustained release of the drug can be attained by water solubilization of the drug accompanied with decomposition of the gel carrier and the formation of sustained release of the drug can be continued over 3 or more days (Adv. Drug Deliv. Rev., 1998 May 4, 31(3) 287-301). In this system, further, by the method of dispersing the hydrogel-constituting polymer aqueous solution in oil and thereby preparing hydrogel fine particles, the size of the fine particles is successfully decreased to be several ten micrometers. However, the size limit is several micrometers by the dispersing method for preparing these hydrogels. Even if such fine particles can be prepared, there is a further problem caused that the hydrogels are aggregated mutually.
The method of utilizing liposome can solve the problems on size and aggregation, but it is difficult to control the period of sustained release because of low stability in the body.
Furthermore, a method of using a high-molecular weight micelle comprising a copolymer of a hydrophobic polyamino acid and a hydrophilic polymer (Japanese Patent No. 2777530) is disclosed. This method can also solve the problems on size and aggregation, but it has a problem of controlling the sustained release properties of a drug because the formation of sustained release of a drug from the high-molecular weight micelle is due to diffusion of the drug contained in the micelle.